PURPOSE: We investigated whether a myocardial perfusion gradient during pharmacologically induced hyperemia also occurred during sympathetic stimulation with cold pressor testing (CPT), which commonly induces a paradoxical coronary vasoconstriction in individuals with coronary risk factors. METHODS: Myocardial blood flow (MBF) was measured in absolute units (ml/g/min) with 13N-ammonia and PET at rest, during CPT, and during pharmacologic vasodilation in 59 participants with coronary risk factors ("at risk") and in 43 healthy individuals (controls). MBF was assessed globally as mean MBF, and in the mid and mid-distal myocardium of the left ventricle (LV). A decrease in MBF from mid to mid-distal LV myocardium was defined as MBF difference indicative of a perfusion gradient. RESULTS: The change in mean MBF to CPT (DeltaMBF) in the at-risk group was significantly reduced compared with controls (0.05+/-0.19 vs 0.31+/-0.20 ml/g/min, p<0.0001), whereas mean MBF during pharmacologic vasodilation in the at-risk group tended to be lower than in controls (1.72+/-0.71 vs 2.00+/-0.64 ml/g/min, p=NS). Absolute MBFs during CPT and pharmacologic vasodilation were significantly lower in the mid-distal than in the mid LV myocardium, resulting in a significant MBF difference in the at-risk group (0.15+/-0.06 and 0.27+/-0.12 ml/g/min, p<0.0001) that was not observed in controls (0.007+/-0.05 and 0.014+/-0.10 ml/g/min, p=NS). In the at-risk group there was a significant correlation between the difference of mid to mid-distal MBF during CPT and that during pharmacologic vasodilation (r=0.43, p<0.004), suggesting functional alterations of epicardial vessels as the predominant cause for the observed MBF difference. CONCLUSION: The relative decrease in MBF from the mid to the mid-distal left-ventricular myocardium suggests an intracoronary pressure decline during CPT and pharmacologic vasodilation, which is likely to reflect an impairment of flow-mediated epicardial vasomotor function.